Process for preparing benzothiophen-2yl boronate

ABSTRACT

A process for preparing the benzothiophen-2-yl boronate of formula (VI)which serves as an intermediate for production of medicaments and for production of medicaments for treatment and/or prophylaxis of proliferative disorders, such as cancer and tumor diseases.

FIELD OF THE INVENTION

The present application relates to a novel and efficient process forpreparing benzothiophen-2-yl boronate of formula (VI)

which serves as an intermediate for production of medicaments and forproduction of medicaments for treatment and/or prophylaxis ofproliferative disorders, such as cancer and tumor diseases.

BACKGROUND OF THE INVENTION

More particularly, the benzothiophen-2-yl boronates of the formula (VI)are suitable for the preparation of compounds of the formula (I)

4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1f]¬[1,2,4]¬triazin-7-yl]methyl}piperazin-2-one or a pharmaceuticallyacceptable salt, hydrate, or solvate thereof, which serves forproduction of medicaments and for production of medicaments fortreatment and/or prophylaxis of proliferative disorders, such as cancerand tumor diseases.

4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-1-benzothiophen-2-yl)pyrrolo[2,1f]¬[1,2,4]¬triazin-7-yl]methyl}piperazin-2-onehas been given the INN ROGARATINIB.

Rogaratinib has valuable pharmacological properties and can be used forthe prevention and treatment of disorders in humans and other mammals.

Rogaratinib is a potent inhibitor of the activity or expression ofreceptor tyrosine kinases, particularly of the FGFR kinases, and mostnotably of the FGFR-1 and FGFR-3 kinases. In certain embodiments, thedisorders relating to the activity of FGFR kinases are proliferativedisorders, in particular cancer and tumor diseases.

Cancer is a leading cause of death worldwide and accounted for 7.6million deaths (around 13% of all deaths) in 2008. Deaths from cancerare projected to continue to rise worldwide to over 11 million in 2030(WHO source, Fact Sheet No. 297, February 2011).

A process for preparation of Rogaratinib as well as the synthesis of thekey intermediate the benzothiophen 2-yl boronates is disclosed in WO2013/087578.

The benzothiophen-2-yl boronates of formula (VI) can conveniently beprepared starting from the substituted thiophenol derivatives of formula(XXIV) (see Scheme 1 below). Alkylation with bromo-acetal (XXV) andsubsequent polyphosphoric acid-mediated cyclization provides thebenzothiophene intermediates of formula (XXVII) which are then metalatedin 2-position and reacted with a trialkyl borate. Alkaline work-upaffords the free (benzothiophen-2-yl)boronic acids of formula (VIa)which may be transformed, if desired, into cyclic boronates, e.g.so-called MIDA boronates of formula (VIb), by standard procedures knownin the art [see, for example, D. M. Knapp et al., J. Am. Chem. Soc. 131(20), 6961-6963 (2009)].

[cf. P. A. Plé and L. J. Marnett, J. Heterocyclic Chem. 25 (4),1271-1272 (1988); A. Venturelli et al., J. Med. Chem. 50 (23), 5644-5654(2007)].

The compounds of the formula (XXIV) are either commercially available,known from the literature, or can be prepared from readily availablestarting materials by adaptation of standard methods described in theliterature. Detailed procedures and literature references for preparingthe starting materials can also be found in the Experimental Part in thesection on the preparation of the starting materials and intermediatesof WO 2013/087578.

-   -   The synthesis according to the above shown scheme has the        general disadvantage that the ring-closure leading to compounds        of the formula (XXVII) needs harsh conditions, such as unusually        high reaction temperatures and unfavourable reagents, such as        syrup-like polyphosphoric acid which can form biphasic systems        with the reaction mixture. These conditions necessitate        considerable safety precautions and substantial engineering        effort on conversion to the industrial scale and thus causes        high production costs.    -   The synthesis according to the above shown scheme has the        disadvantage of formation of impurities of high structural        similarity due to mentioned drastic reaction conditions, which        only can be purged by extensive purification efforts on        compounds of the formula (XXVII) or at following stages of the        synthesis. This leads to additional effort, cost and significant        reduction of yield—especially on industrial scale. These        impurities even may not be purged to the extent that is needed        for pharmaceutical products according to the appropriate        regulatory guidelines.

During the preparation of the benzothiophen-2-yl boronates of theformula (VI) via ring closure of (1) to (2):

according to the process as outlined in scheme 1 the formation ofimpurities was observed that comply with structures of the formulas 3.1to 3.6 according to mass spectroscopy.

These impurities could be traced back to impurities that comply withstructures of the formulas 4.1 to 4.6 in themethoxy-methyl-benzothiophene intermediate (2).

These impurities are formed during the ring-closure process with PPA athigh temperatures and were purged by fractionated high vacuumdistillation of (2), which reduces the yield to 14-20% on industrialscale, but still not leads to impurity levels that match therequirements for APIs in late stage clinical development.

It is an object of the present invention to provide an efficient processwith high yield for preparation of benzothiophen-2-yl boronates of theformula (VI)

as a key component for an efficient process with high yield forpreparation of compound of the formula (I)

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

SUMMARY OF THE INVENTION

The present invention relates to a method of preparing a compound offormula (VI):

comprising the following steps:step 5:wherein a compound of formula (VII):

is allowed to react, by dissolution of compound of formula (VII) in aninert solvent such as THF, and addition of a metal organic base such asa n-butyl lithium solution and a trialkyl borate such as tri iso-propylborate, optionally in a solvent, such as THF, thereby providing acompound of formula (VI):

said compound of formula (VII):

being prepared by the following step 4:wherein a compound of formula (X):

is allowed to react, optionally in the presence of an inert solvent,such as THF for example, with one or more reducing agents, such as asodium-bis(2-methoxy-ethoxy)-aluminium-dihydride solution for example,thereby providing a compound of formula (IX):

and allowing the compound of formula (IX) to react with aqueous HCl inthe presence of a solvent such as toluene for example, thereby providinga compound of formula (VIII):

and allowing the compound of formula (VIII) to react with one or morereducing agents, such as asodium-bis(2-methoxy-ethoxy)-aluminium-dihydride solution for example,thereby providing a compound of formula (VII).

The present invention also relates to a compound selected from:

DETAILED DESCRIPTION OF THE INVENTION

As stated above, it is an object of the present invention to provide anefficient process with high yield for preparation of benzothiophen-2-ylboronates of the formula (VI)

as a key component for an efficient process with high yield forpreparation of compound of the formula (I)

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

This object is achieved in accordance with the present invention, asfollows. Scheme 2 below illustrates the individual reaction steps by wayof example.

One aspect of the present invention is directed to the preparation ofbenzothiophen-2-yl boronate of the formula (VI) free from the impurities(3.1 to 3.6) which are shown above by using the synthetic pathwayaccording to Scheme 2 which avoids the ring closure of the thiophenering system using high temperature friedel-crafts-like conditions andthe use-of poly-phosphoric acid. Instead benzothiophene derivative withthe formula (X) is formed via dehydrating conditions and is thenconverted to the benzothiophen-2-yl boronates of the formula (VI) viathe benzothiophene derivative (VII). This moderate conditions lead tohigh conversion and impurities from this process can be well purgedduring vacuum distillation of (VII). Despite increased number ofsynthetic steps overall yield is significantly improved and standardpilot plant equipment can be used, leading to significant reduction ofproduction cost.

The ring closure disclosed in steps 1 and 2 below are already known in amodified form from EP 2338887 A1 Reference Examples 12 and 13, as wellas a further modified version from JACS Vol 129, No.45, 2007 Boger etal.

The following disadvantages are connected with this lab scale processesleading to ethyl 7-acetoxy-3-methylbenzo[b]thiophene-5-carboxylateaccording to Boger, et al.: Low overall yields are observed—probably dueto decomposition of the thiophen-aldehyde under basic reactionconditions during the condensation reaction. Therefore high amounts ofsuccinate reagents were applied (e.g. 6 equivalents). In the ringclosure reaction under dehydrating conditions a large access of aceticacid anhydride was applied by using acetic acid anhydride as a solventat high reaction temperatures of up to 140° C. As a result the productEthyl 7-Acetoxy-3-methylbenzo[b]thiophene-5-carboxylate could only beisolated in 40% yield after purification by chromatography. Furthermorea reaction in refluxing acetic acid anhydride would need significantsafety and engineering considerations during scale-up.

We unexpectedly could achieve high conversion in the condensationreaction towards intermediate (XIII) by changing the order of additionthrough adding the thiophene-3-aldehyde to a mixture of succinic esterand sodium methanolate. Under these conditions only a slight excess ofsuccinate (2.5. equivalents) has to be applied. Side components andexcess reagents can be purged at this early stage by crystallization ofthis intermediate e.g. from toluene, avoiding chromatographicpurification on a later stage.

Furthermore the ring closure under dehydrating conditions could becompleted with a low excess of acetic acid anhydride diluted by tolueneas an inert solvent at moderate temperatures of only 75° C. within 7hours. These conditions facilitate less side reactions and safe work-upof the reaction mass on industrial scale. If the crude intermediatebenzothiophene carboxylic ester (XII) is then subjected tosaponification with aqueous NaOH in MeOH, followed by neutralizationwith an acid, the benzothiophene carboxylic acid can be isolated in highyield and purity as a solid.

A first aspect of the present invention is directed to a process for thepreparation of benzothiophen-2-yl boronates of formula (VI).

Step 1:

According to the first aspect of the present invention the reaction of(XV) and (XIV) to (XIII) as shown above is carried out by condensationof (XV) with (XIV). This is done by adding a solution of an alkalialcoholate, such as sodium methanolate, in an alcohol, preferablymethanol to a solution of dimethyl succinate at 25-40° C. Othersuccinate esters can be used in place of (XV), as the esters are cleavedduring following steps.

The mixture is heated to reflux and a solution of thiophene-3-aldehydeis added. After complete conversion the mixture is hydrolyzed byaddition of water and the product is extracted with toluene. (or othernon-water miscible solvents) After removal of the solvent the crude(XIII) is purified by crystallization and/or reslurry from toluene (orother suitable solvents).

-   -   This process has the advantage of high conversion related to the        aldehyde by slow addition of the thiophene-3-aldehyd to the        reaction mixture.    -   This process has the advantage of applying reduced excess of        dimethyl succinate for full conversion.    -   This process has the advantage of giving a very pure and solid        intermediate (XIII) after purification by crystallization or        /reslurry, contributing to avoidance of purification on later        stages by e.g. preperative chromatography.

Step 2:

According to the first aspect of the invention, the reaction of (XIII)to the carboxylic acid intermediate (XI) via (XII) as shown in Step 2 iscarried out by ring-closure to the benzothiophen derivative (XII) underdehydrating conditions and hydrolysis of the ester moieties yielding the7-hydroxy-1-benzothiophene-5-carboxylic acid (XI). This is done byheating (XIII) with acetic acid anhydride and sodium acetate in tolueneat 70-75° C. for 7 h (other dehydrating agents: e.g. acid anhydrides(trifluoracetic acid anhydride), methyl chloro formate; other bases thansodium acetate (potassium acetate; T & t can be varied for all processsteps). The mixture is hydrolyzed by addition of water at 25-30° C. Theorganic phase is separated, washed with water, again, and the solvent ispartially removed by distillation under reduced pressure. The remainingsolution of (XII) in toluene is diluted with MeOH and water and anaqueous sodium hydroxide solution (other bases, mainly inorganic) isslowly added at temperatures below 45° C. and finally heated to 50-55°C. for 5 h. The aqueous phase is separated and further diluted withwater and the product is precipitated by addition of a strong proticacid such as HCl, HNO₃, sulfonic acids, CH₃COOH and H₂SO₄, preferablyH₂SO₄ at 10-15° C. till a pH of 2-3 is reached. The suspension is heatedto 40-45° C. and cooled to 25-30° C. within 2 h to improve filtrationbehavior of the product, and isolated by filtration.

-   -   This process has the advantage of increased process safety for        industrial scale by not using a large excess of acetic acid        anhydride as a solvent, but a limited excess by dilution in        toluene. Safe work-up is achieved by controlled release of        energy during hydrolyzation of acetic acid anhydride under        diluted conditions.    -   This process has the advantage of giving reduced amounts of side        products by using only moderate reaction temperatures during the        ring closure step towards (XII).    -   This process has the advantage of acceptable filtration times on        industrial scale during isolation of (XI) by improving solid        state properties during temperature treatment before isolation.    -   This process has the advantage of yielding a well crystalizing        solid product of intermediate (XI) with very high purity in very        good yield, avoiding additional purification steps on        intermediate (XII) or later stages of the synthesis.

Step 3:

According to the first aspect of the present invention, the reaction of(XI) to methyl 7-methoxy-1-benzothiophene-5-carboxylate (X) as shown inscheme is carried out by methylating the ester and phenol moiety. Thisis done by dissolving (XI) in a mixture of acetone and toluene (othersolvents). After addition of a potassium carbonate (other basesinorganic, amines . . . ) the suspension is heated to 50-60° C. anddimethylsulfate (other methylating agents: methyl iodide) is slowlyadded. After full conversion the solvent is partially distilled of at85° C. and water is added. Phases are separated and aqueous phase isadditionally extracted with toluene. Combined organic phases are washedwith water and the solvent is removed under reduced pressure at 60° C.The crude product is submitted to the next step.

Step 4:

According to the first aspect of the present invention, the reaction of(X) to 7-methoxy-5-methyl-1-benzothiophene (VII) is done by reduction ofthe ester moiety to the methyl group yielding (VII). This ispreferentially achieved by stepwise reduction through reducing the estermoiety of (X) to the alcohol (IX), followed by chlorination of thealcohol moiety to (VIII), followed by reduction to (VII) as shown inStep 4. This is done by dissolving the crude product (X) in an inertsolvent such as ethers, for example dioxane Me-THF, CPME, and MTBE,aromatic & aliphatic hydrocarbons, for example benzene, toluene, xylolcyclohexane; preferably THF is used and addition ofsodium-bis(2-methoxy-ethoxy)-aluminium-dihydride (Red-Al®) solution intoluene at 25-30° C. Other suitable reducing agents include hydrogen(with a suitable catalyst), LAH, boranes and silanes.

The mixture is hydrolyzed by addition of aqueous sodium hydroxidesolution (other aqueous bases) and the product is extracted with toluene(other no-water miscible solvents or precipitated/crystallized byanti-solvent addition) and isolated by removing the solvent underreduced pressure at 60° C.

Crude (IX) is dissolved in toluene and at 50-55° C. aqueous HCl isslowly added. Other chlorinated agents such as SOCl₂ may be utilized.After complete conversion the mixture is hydrolyzed with aqueous sodiumbicarbonate solution. The organic phase is dried by treatment withbrine, Na₂SO₄ and azeotropic drying by removing the solvent underreduced pressure at 60° C.

Also, other leaving groups can be used as an alternative chlorine instructure (VIII), such as Br, I, F, RSO₃, for example.

Crude product (VIII) is dissolved in an inert solvent such as ethers,for example Dioxane Me-THF, CPME, and MTBE, aromatic & aliphatichydrocarbons, for example benzene, toluene, xylol cyclohexane;preferably THF is used and a reduced using a reducing agent such assodium-bis(2-methoxy-ethoxy)-aluminum-dihydride (Red-Al®) solution intoluene is added at 25-30° C. Other suitable reducing agents includehydrogen (with a suitable catalyst), LAH, boranes and silanes.

The mixture is hydrolyzed by addition of aqueous sodium hydroxidesolution (other aqueous bases) and the product is extracted with toluene(other no-water miscible solvents or precipitated/crystallized byanti-solvent addition) and isolated by removing the solvent underreduced pressure at 60° C. (VIII) is purified by distillation undervacuum at 125-160° C.

-   -   This process has the advantage of giving        7-methoxy-5-methyl-1-benzothiophene (VII) in high yield and high        purity without impurities according to Scheme 1 which are        critical in regard of the quality of the final pharmaceutical        ingredient (I) for clinical applications and cannot be easily        purged in one of the following process steps towards (I).    -   This process has the advantage of giving        7-methoxy-5-methyl-1-benzothiophene (VII), using standard        multipurpose equipment and safe reagents on industrial scale.        The use of drastic reaction conditions like high        temperatures >160° C. and unfavourable reagents like syrup-like        polyphosphoric acid, which is not completely dissolved in the        reaction mixture, is avoided. Very costly safety and engineering        considerations on industrial scale are therefore avoided.

Step 5:

According to the first aspect of the present invention, the reaction of(VII) to benzothiophen-2-yl boronates of the formula (VI) is done byborylation. (VII) is dissolved in an inert solvent such as THF andmetallated by addition to a metal organic base such as n-butyl lithiumsolution in THF/hexane at −73 to −80° C. After stirring the reactionmass for 30 minutes triisopropyl borate is slowly added at −73 to −80°C. After a reaction time of 30 minutes, the mixture is hydrolyzed withaqueous potassium hydroxide solution at <10° C. and phases are separatedat 20-30° C. Aqueous phase is washed with toluene and product isprecipitated by addition of aqueous sulfuric acid solution at 0-5° C.(other acids). (VI) is isolated by filtration and washed with water. Theproduct is reslurried with a solvent such as cyclohexane at 40-45° C.,isolated and dried at 40-45° C. at reduced pressure.

-   -   This process has the advantage of giving        (7-methoxy-5-methyl-1-benzothiophen-2-yl) boronic acid (VI) in        high yield and high purity without impurities according to        Scheme 1 which are critical in regard of the quality of the        final pharmaceutical ingredient (I) for clinical applications        and cannot be easily purged in one of the following process        steps towards (I).

According to an alternate embodiment of the first aspect of the presentinvention, a route from intermediate (XII) to (X) is shown in thefollowing Scheme 3:

An alternative embodiment of this first aspect of the present inventionis the conversion of intermediate (XII) to (X) via intermediate (XV).Only the acetyl function of (XII) is selectively hydrolyzed to theintermediate (XV) by applying a weaker base compared to the process forthe preparation of intermediate (XI). This is done by mixing (XII) withpotassium carbonate in ethanol at elevated temperature. The reactionmass is hydrolyzed by addition of aqueous hydrogen chloride solution andthe product is extracted with methyl t-butyl ether. (XV) is obtainedafter removal of the solvent at reduced pressure.

The reaction of (XV) to methyl 7-methoxy-l-benzothiophene-5-carboxylate(X) is carried out by treatment with a methylating agent with or withoutpresence of a base. This is done by mixing (XV) with potassium carbonateand dimethyl sulfate in 2-butanone and stirring at room temperature.After complete reaction an aqueous solution of ammonia and methylt-butyl ether is added. The organic phase is concentrated at reducedpressure yielding (X).

-   -   This alternative process has the disadvantage of avoiding a well        crystalizing solid product of intermediate (XI).    -   This alternative process has the advantage of allowing        telescoping XV as a solution and applying less amount of toxic        methylating agent at moderate temperature.

In an alternative embodiment of the first aspect of the presentinvention, the route from intermediate (XI) to7-methoxy-5-methyl-1-benzothiophene (VII) is shown in the following

In this route (XIII) is first reduced in a single step giving (XVII) orin 2 steps giving intermediate (XVII) via intermediate (XVI). (XVII) isthen methylated to (VII).

Salts for the purposes of the present invention are preferablypharmaceutically acceptable salts of the compounds according to theinvention (for example, see S. M. Berge et al., “Pharmaceutical Salts”,J. Pharm. Sci. 1977, 66, 1-19). Salts which are not themselves suitablefor pharmaceutical uses but can be used, for example, for isolation orpurification of the compounds according to the invention are alsoincluded.

Pharmaceutically acceptable salts include acid addition salts of mineralacids, carboxylic acids and sulfonic acids, for example salts ofhydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,toluenesulfonic acid, naphthalenedisulfonic acid, formic acid, aceticacid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid,malic acid, citric acid, fumaric acid, maleic acid, and benzoic acid.

Pharmaceutically acceptable salts also include salts of customary bases,such as for example and preferably alkali metal salts (for examplesodium and potassium salts), alkaline earth metal salts (for examplecalcium and magnesium salts), and ammonium salts derived from ammonia ororganic amines, such as illustratively and preferably ethylamine,diethylamine, triethylamine, N,N-diiso-propylethylamine,monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol,diethylaminoethanol, procaine, dicyclohexylamine, dibenzylamine,N-methylmorpholine, N-methylpiperidine, arginine, lysine, and1,2-ethylenediamine.

Solvates in the context of the invention are designated as those formsof the compounds according to the invention which form a complex in thesolid or liquid state by stoichiometric coordination with solventmolecules. Hydrates are a specific form of solvates, in which thecoordination takes place with water. Hydrates are preferred solvates inthe context of the present invention.

The compounds of this invention may, either by nature of asymmetriccenters or by restricted rotation, be present in the form of isomers(enantiomers, diastereomers). Any isomer may be present in which theasymmetric center is in the (R)-, (S)-, or (R,S)-configuration.

All isomers, whether separated, pure, partially pure, or in racemicmixture, of the compounds of this invention are encompassed within thescope of this invention. The purification of said isomers and theseparation of said isomeric mixtures may be accomplished by standardtechniques known in the art. For example, diastereomeric mixtures can beseparated into the individual isomers by chromatographic processes orcrystallization, and racemates can be separated into the respectiveenantiomers either by chromatographic processes on chiral phases or byresolution.

In addition, all possible tautomeric forms of the compounds describedabove are included according to the present invention.

The present invention also encompasses all suitable isotopic variants ofthe compounds according to the invention. An isotopic variant of acompound according to the invention is understood to mean a compound inwhich at least one atom within the compound according to the inventionhas been exchanged for another atom of the same atomic number, but witha different atomic mass than the atomic mass which usually orpredominantly occurs in nature. Examples of isotopes which can beincorporated into a compound according to the invention are those ofhydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine andiodine, such as ²H (deuterium), ³H (tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸F,³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I. Particular isotopic variants of acompound according to the invention, especially those in which one ormore radioactive isotopes have been incorporated, may be beneficial, forexample, for the examination of the mechanism of action or of the activecompound distribution in the body. Due to comparatively easypreparability and detectability, especially compounds labelled with ³Hor ¹⁴C isotopes are suitable for this purpose. In addition, theincorporation of isotopes, for example of deuterium, can lead toparticular therapeutic benefits as a consequence of greater metabolicstability of the compound, for example an extension of the half-life inthe body or a reduction in the active dose required. Such modificationsof the compounds according to the invention may therefore in some casesalso constitute a preferred embodiment of the present invention.Isotopic variants of the compounds according to the invention can beprepared by processes known to those skilled in the art, for example bythe methods described below and the methods described in the workingexamples, by using corresponding isotopic modifications of theparticular reagents and/or starting compounds therein.

Unless otherwise noted, suitable bases for the coupling reactions, wherenecessary, are in particular alkali carbonates, such as sodium,potassium or caesium carbonate, alkali phosphates, such as sodium orpotassium phosphate, or alkali fluorides, such as potassium or caesiumfluoride. Usually, these bases are employed as aqueous solutions. Thereactions are carried out in organic solvents that are inert under thereaction conditions. Preferably, water-miscible organic solvents, suchas 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, acetonitrile,N,N-dimethylformamide (DMF) or dimethylsulfoxide (DMSO), are employedbut other inert solvents, such as dichloromethane or toluene, may alsobe used.

Unless otherwise noted, condensing agents suitable for the processsteps, where necessary, include, for example, carbodiimides such asN,N′-diethyl-, N,N′-dipropyl-, N,N′-diisopropyl-,N,N′-dicyclo-hexylcarbodiimide (DCC) orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC), phosgenederivatives such as N,N′-carbonyldiimidazole (CDI) or isobutylchloroformate, α-chloroenamines such as1-chloro-2-methyl-l-dimethylamino-l-propene, phosphorus compounds suchas propane-phosphonic anhydride, diethyl cyanophosphonate,bis(2-oxo-3-oxazolidinyl)phosphoryl chloride,benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP) or benzo-triazol-1-yloxy-tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), and uronium compounds such asO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU),2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TPTU), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) orO-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TCTU), if appropriate in combination with furtherauxiliaries, such as 1-hydroxybenzotriazole (HOBt) orN-hydroxysuccinimide (HOSu), and/or bases such as alkali carbonates, forexample sodium or potassium carbonate, or organic amine bases, such astriethylamine, N-methylpiperidine, N-methylmorpholine (NMM),N,N-diisopropyl-ethylamine (DIPEA), pyridine or4-N,N-dimethylaminopyridine (DMAP). Preference is given to usingO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) in combination with N,N-diisopropylethylamine (DIPEA) andoptionally 1-hydroxybenzotriazole (HOBt).

Unless otherwise noted, acceptable inert solvents for process (wherenecessary) are, for example, ethers such as diethyl ether, tert-butylmethyl ether, tetrahydrofuran (THF), 1,4-dioxane or 1,2-dimethoxyethane,hydrocarbons such as benzene, toluene, xylene, hexane or cyclohexane,halogenated hydrocarbons such as dichloromethane, trichloromethane,carbon tetrachloride, 1,2-dichloroethane, trichloroethylene orchlorobenzene, or other solvents such as acetone, acetonitrile, ethylacetate, pyridine, dimethylsulfoxide (DMSO), N,N-dimethylformamide(DMF), N,N′-di-methylpropylene urea (DMPU) or N-methylpyrrolidinone(NMP). It is also possible to use mixtures of these solvents. Preferenceis given to using dichloromethane, tetrahydrofuran,N,N-dimethylformamide or mixtures thereof.

EXAMPLES Abbreviations and Acronyms

Ac acetyl

Ac₂O acetic anhydride

AcOH acetic acid

aq. aqueous (solution)

Boc tert-butoxycarbonyl

br. broad (¹H-NMR signal)

Bu butyl

cat. catalytic

conc. concentrated

d doublet (¹H-NMR signal)

DBDMH 1,3-dibromo-5,5-dimethylhydantoin

DCI direct chemical ionization (MS)

DCM dichloromethane

Dess-Martin periodinane1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one

DIPEA N,N-diisopropylethylamine

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

EI electron impact ionization (MS)

eq. equivalent(s)

ESI electro-spray ionization (MS)

Et ethyl

EtOAc ethyl acetate

GC-MS gas chromatography-coupled mass spectroscopy

h hour(s)

Hal halogen

¹H-NMR proton nuclear magnetic resonance spectroscopy

HPLC high performance liquid chromatography

iPr isopropyl

LC-MS liquid chromatography-coupled mass spectroscopy

Me methyl

MeOH methanol

min minute(s)

MS mass spectroscopy

m/z mass-to-charge ratio (MS)

NBS N-bromosuccinimide

n-Bu n-butyl

NCS N-chlorosuccinimide

of th. of theory (chemical yield)

Pd/C palladium on charcoal

PdCl₂(dppf) [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

Pd(dba)₂ bis(dibenzylideneacetone)palladium

Ph phenyl

PPA polyphosphoric acid

q quartet (¹H-NMR signal)

quant. quantitative (yield)

rac racemic

R_(f) TLC retention factor

RP reverse phase (HPLC)

rt room temperature

R_(t) retention time (HPLC)

s singlet (¹H-NMR signal)

sat. saturated (solution)

t triplet (¹H-NMR signal)

TBAF tetra-n-butylammonium fluoride

TBDMS tert-butyldimethylsilyl

TBTUN-[(1H-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methyl-methanaminiumtetrafluoroborate

tBu tert-butyl

tert tertiary

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

LCMS (Method 1): HSST3

Instrument: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLCHSS T3 1.8 μm 50×1 mm; eluent A: 1 l water+0.25 ml 99% formic acid,eluent B: 1 l acetonitrile+0.25 ml 99% formic acid; gradient: 0.0 min90% A→1.2 min 5% A→2.0 min 5% A; flow rate: 0.40 ml/min; UV detection:208-400 nm.

LCMS (Method 2): MHZ-QP-Gold

Instrument: Micromass Quattro Premier mit Waters UPLC Acquity system;column: Thermo Hypersil GOLD 1.9 μ 50×1 mm; eluent A: 1 l water+0.5 ml50% formic acid, eluent B: 1 l acetonitrile+0.5 ml 50% formic acid;gradient: 0.0 min 97% A→0.5 min 97% A→3.2 min 5% A→4.0 min 5% A oven:50° C.; flow rate: 0.3 ml/min; UV detection: 210 nm.

LCMS (Method 3): MCW-FT-MS-M1

Instrument: Thermo Scientific FT-MS UHPLC+ system; Thermo ScientificUltiMate 3000; column: Waters, HSST3, 2.1×75 mm, C18 1.8 μm; eluent A: 1l water+0.01% formic acid; eluent B: 1 l acetonitrile+0.01% formic acid;gradient: 0.0 min 10% B→2.5 min 95% B→3.5 min 95% B; oven: 50° C.; flowrate: 0.90 ml/min; UV detection: 210 nm/ Optimum Integration Path210-300 nm

LCMS (Method 4): MCW SO-HSST3 LONG

Instrument: Waters ACQUITY SQD UPLC system; column: Waters Acquity UPLCHSS T3 1.8 μ 50×1 mm; eluent A: 1 l water+0.25 ml 99% formic acid ,eluent B: 1 l acetonitrile+0.25 ml 99% formic acid; gradient: 0.0 min95% A→6.0 min 5% A→7.5 min 5% A oven: 50° C.; flow rate: 0.35 ml/min; UVdetection: 210-400 nm.

GCMS (Method 1): DSO-II

Instrument: Thermo Scientific DSQII, Thermo Scientific Trace GC Ultrasystem; column: Restek RTX-35MS, 15 m×200 μm×0.33 μm; constant heliumflow: 1.20 ml/min; oven: 60° C.; inlet: 220° C.; gradient: 60° C., 30°C./min→300° C. (hold time 3.33 min).

HPLC Method 1

System: High performance liquid chromatograph equipped with gradientpumps, UV detector & attached with data recorder and integratorsoftware; column: Zorbax Eclipse XDB C18 (150 mm*3 mm, 3.5 μm); flow:0.5 mL/min; column temperature: 30° C.; injection volume 10 μL,detection 226 nm, run time: 30 min; mobile phase A: 1.15 g NH₄H₂PO₄ and1.16 g H₃PO₄ (85%) in 1 L mili-Q water; mobile phase B: acetonitrile;gradient:

Time Mobile phase-A Mobile phase-B (min) (% v/v) (% v/v) 0.0 95 5 5.0 4060 15.0 30 70 25.0 20 80 25.1 95 5 30.0 95 5 30.01 Stop

Example 1 3-(Methoxycarbonyl)-4-(3-thienyl)but-3-enecarboxylic acid(XIII)

256 kg of dimethyl succinate are initially charged in 296 L of methanol.332 kg of NaOMe (30% in MeOH) are added over a period of 2 h at atemperature from 25-40° C. The reaction mixture is heated to 65-70° C.and a solution of 98.5 kg of thiophene-3-aldehyde in 20 L of methanol isadded over a period of 4 h. The mixture is further stirred for 2 h andsubsequently cooled to 30-35° C. The solvent is distilled off underreduced pressure at <55° C. (residual volume ca. 400 L). The mixture iscooled to 10-30° C. and 296 L of toluene and 788 L of water are added.The phases are separated and the aqueous phase is adjusted between pH1-3 with conc. HCl. The aqueous phase is extracted a further three timeswith a total of 789 L of toluene and the combined organic phases arewashed with a solution of 98.5 kg of NaCl in 493 L of water. The solventis distilled off under reduced pressure at <60° C. and 197 L of tolueneare added to the residue at 35-40° C. The mixture is cooled to −5° C.and filtered. The filter residue is washed with 49 L of toluene and 197L of hexane and then dried under reduced pressure at 45-50° C. 128.9 kgof 3 are obtained in 65% yield.

The crude product from laboratory experiments prepared analogously tothe above procedure—but on a smaller scale—was additionally purifiedaccording to the following method for analytical characterization:

45 g of crude product in 90 mL of toluene were stirred at 40° C. for 1 hand subsequently cooled to −5° C. over a period of 2 h and isolated on afilter. The filter residue was further washed with cold toluene andhexane and dried in a vacuum drying cabinet at 40° C. 25.6 g of (XIII)were obtained and characterized:

¹H NMR (600 MHz, DMSO-d₆) δ ppm 3.53 (s, 2H), 3.74 (s, 3H), 7.31 (dd,J=4.95, 1.10 Hz, 1H), 7.67 (dd, J=4.95, 2.93 Hz, 1H), 7.75 (s, 1H), 7.86(d, J=2.57 Hz, 1H), 12.53 (br s, 1H)

LCMS (method 3): R_(t)=1.27 min; MS (ESIpos): m/z=227 (M+H)⁺

Example 2 Methyl 7-acetoxy-1-benzothiophene-5-carboxylate (XII)

73.1 kg of (XIII) are initially charged in 731 L of toluene and 115.5 kgof acetic anhydride and 32.2 kg of sodium acetate are added. Thereaction mixture is heated to 70-75° C. for 7 h. 366 L of water areadded at 25-30° C. and the phases separated and the organic phase iswashed with 366 L of water. The organic phase is concentrated underreduced pressure at <60° C. up until a residual volume of 300-360 Lremains. The crude product is used as a solution in the next stage.

The analytical characterization was carried out on a sample from thefollowing laboratory procedure:

204 g of intermediate (XIII) are initially charged in 720 mL of tolueneand 230 g of acetic anhydride and 89 g of sodium acetate are added. Thereaction mixture is heated to 70-75° C. for 7 h. After cooling, thereaction mixture is filtered, the filtrate is washed with 1 L of waterand the phases are separated. The organic phase is washed with 1 L ofsat. aqueous NaCl solution. The organic phase is concentrated underreduced pressure at <60° C., and 2× 200 mL of ethanol are added and themixture again concentrated. 202 g of crude product 4 are obtained, andmay be used without further purification in the next stage.

10 g of the crude product are recrystallised from 50 mL of diisopropylether and dried in the drying cabinet at 40° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.41 (s, 3H), 3.91 (s, 3H), 7.70 (d,J=5.38 Hz, 1H), 7.76 (s, 1H), 7.95 (d, J=5.38 Hz, 1H), 8.46 (s, 1H)

LCMS (method 4): R_(t)=2.72 min; MS (ESIpos): m/z=251 (M+H)⁺

Example 3 7-Hydroxy-1-benzothiophene-5-carboxylic acid (XI)

146 L of methanol and 292 L of water are added to the concentrated crudesolution of (XII) at 25-30° C. and a solution of 77.5 kg of NaOH in 366L of water are added at <45° C. over a period of 1.5 h. The reactionmixture is heated to 50-55° C. for 5 h. The phases are separated and theaqueous phase is further diluted with 73 L of water. The aqueous phaseis acidified to pH 2-3 with semi-concentrated sulphuric acid at 10-15°C. and then heated to 40-45° C. for a further 1 h. After slow cooling to25-30° C. over a period of 2 h, the product is isolated on a centrifugalfilter and washed with 219 L of water. After drying in the warm airdryer at 60-65° C., 57.5 kg of intermediate (XI) were obtained (yield:92%).

The analytical characterization was carried out on a sample from thefollowing laboratory procedure:

2.0 g of 4 were initially charged in 15 mL of ethanol and 5 mL of THF atroom temperature and 20 mL of aqueous sodium hydroxide solution (2molar) were added. The mixture is heated to 50° C. for 3 h and then 50mL of ethyl acetate and 10 mL of toluene are added. The phases areseparated and the aqueous phase is acidified with 3.6 g ofsemi-concentrated sulphuric acid. The suspension is cooled to 0° C. andfiltered. The filter residue is washed with water and dried in thevacuum drying cabinet at 40° C. 1.4 g (90%) of (XI) are obtained andcharacterized:

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.50 (dt, J=3.55, 1.77 Hz, 1H), 2.54 (s,1H) 3.32 (s, 3H), 7.33 (d, J=1.10 Hz, 1H), 7.53 (d, J=5.38 Hz, 1H), 7.79(d, J=5.38 Hz, 1H), 8.00 (d, J=1.34 Hz, 1H), 10.64 (s, 1H), 12.79 (s,1H)

LCMS (method 1): R_(t)=0.67 min; MS (ESI neg): m/z=194 (M−H)

Example 4 Methyl 7-methoxy-1-benzothiophene-5-carboxylate (X)

Method A

61.0 kg of intermediate (XI) are initially charged in 244 L of acetoneand 427 L of toluene and 130.2 kg of K₂CO₃ are added. The suspension isheated to 50-60° C. and 79.2 kg of dimethyl sulphate are added over aperiod of 1 h. The mixture is stirred for a further 8 h at thistemperature and the solvent is subsequently distilled off at 85° C.until no further distillate passes over.

After cooling to 25-30° C., 610 L of water are added and the phases areseparated. The aqueous phase is extracted with 244 L of toluene, thecombined organic phases are washed with 305 L of water and the solventis distilled off under reduced pressure at 60° C. The crude product (X)is used without further purification in the next stage.

Method B

18.5 g of intermediate (XV) are initially charged in 220 mL of2-butanone and 18.4 g of potassium carbonate are added and the mixturestirred at room temperature for 5 minutes. 8.4 mL of dimethyl sulphateare then added and the mixture is stirred at room temperature for 5 h.To the suspension are added 26.7 mL of 28% ammonia solution, 220 mL ofwater and 220 mL of methyl t-butyl ether and the mixture is stirred for1 h. The phases are separated and the aqueous phase is extracted with3×220 mL of methyl t-butyl ether. The combined organic phases are driedover sodium sulphate and concentrated under reduced pressure at 40° C.Intermediate (X) is obtained in quantitative yield. For analyticalcharacterization a combined sample from several laboratory experimentswas purified by preparative chromatography and characterized:

11.4 g of crude product (X) were purified chromatographically on ca. 370g of silica gel to using n-heptane and ethyl acetate (95:5 to 90:10).7.4 g of 6 were obtained by concentrating the main fraction andcharacterized analytically:

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.91 (s, 3H), 4.03 (s, 3H), 7.40 (s,1H), 7.61 (d, J=5.26 Hz, 1H), 7.88 (d, J=5.38 Hz, 1H), 8.19 (s, 1H)

GCMS (method 1): R_(t)=6.51 min; MS: m/z=222 (M)⁺

Example 5 (7-methoxy-1-benzothiophen-5-yl)methanol (IX)

The crude product (X) from the preceding stage is dissolved in 244 L ofTHF and 159 kg of a 60% solution of sodium bis(2-methoxyethoxy)aluminiumdihydride (Red-Al®) in toluene is added at 25-30° C. over a period of 3h. The reaction mixture is stirred for a further 3 h, cooled to 0-5° C.and subsequently hydrolysed with a solution of 61.0 kg of NaOH in 610 Lof water at <25° C. 122 L of toluene is then added at 25-30° C., thephases are separated and the aqueous phase is extracted with 305 L oftoluene. The combined organic phases are washed with a solution of 61 kgof NaCl in 305 L of water and concentrated under reduced pressure at 60°C. Intermediate (IX) is used without further purification in thefollowing stage.

A sample for analytical characterisation was prepared according to thefollowing procedure:

26.3 g of (X) are dissolved in 230 mL of THF and 25.2 mL of a 2.4 molarsolution of lithium aluminium hydride in THF are added at 10-20° C. overa period of 10 min. The reaction mixture is stirred for a further lh andsubsequently hydrolysed with 84 mL of aqueous hydrochloric acid (1M) inan ice bath.

130 mL of methyl tent-butyl ether are added and adjusted to pH 1 with 80mL of aqueous hydrochloric acid (2M). The aqueous phase is separated andextracted with methyl tert-butyl ether. The combined organic phases arewashed with 50 mL of 5% aqueous saline solution, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue is purified bypreparative chromatography on 900 g of silica gel (eluent n-heptane:ethyl acetate 70:30 to 65:35). 18.5 g (92%) of product (IX) are obtainedas an oil.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.95 (s, 3H), 4.61 (d, J=5.75 Hz, 2H),5.25 (t, J=5.75 Hz, 1H), 6.90 (s, 1H), 7.37-7.45 (m, 2H) 7.70 (d, J=5.26Hz, 1H)

GCMS (method 1): R_(t)=6.45 min; MS: m/z=194 (M)⁺

Example 6 5-(Chloromethyl)-1-benzothiophen-7-yl methyl ether (VIII)

Intermediate (IX) is heated to 50-55° C. in 852 L of toluene and 609 Lof concentrated aqueous HCl are added over a period of 90 min. Themixture is stirred for a further 6 h and then cooled to 25-30° C. Thephases are separated and the organic phase is added to a solution of54.8 kg of NaHCO₃ in 609 L of water. The organic phase is separated,washed with 61 kg of NaCl in 304 L of water and 60.9 kg of Na₂SO₄ areadded. The suspension is filtered and the filter cake is washed with 61L of toluene. The solvent is distilled off under reduced pressure at<60° C. and (VIII) is used without further purification in the nextstage.

A sample for analytical characterization was produced according to thefollowing procedure:

6.3 ml of thionyl chloride were added to 14.0 g of intermediate (IX) in210 mL of toluene at room temperature and the mixture is stirred for 2h. The reaction mixture is concentrated under reduced pressure at 60° C.and toluene is added twice more, 150 ml each time, and the mixtureconcentrated.

The residue is taken up in 230 mL of methyl tent-butyl ether and 150 mLof water. 30 mL of 10% aqueous saline solution are added and the mixtureneutralized with 15 mL of saturated aqueous NaHCO₃ solution. The organicphase is washed with 30 mL of 10% aqueous saline solution andconcentrated under reduced pressure. For drying, the residue is treatedtwice with a little ethyl acetate and concentrated. 14.20 g (93%) ofproduct (VIII) are obtained as an oil.

GCMS (method 1): R_(t)=6.29 min; MS: m/z=212 (M)⁺

Example 7 7-Methoxy-5-methyl-1-benzothiophene (VII)

The crude product (VIII) from the preceding stage is dissolved in 304 Lof THF and 237.5 kg of a 60% solution of sodiumbis(2-methoxyethoxy)aluminium dihydride (Red-Al®) in toluene are addedat 20-35° C. over a period of 4 h. The reaction mixture is stirred for afurther 2 h, cooled to 0-5° C. and subsequently a solution of 91.3 kg ofNaOH in 913 L of water is added slowly at <25° C. 122 L of toluene arethen added at 25-30° C., the phases separated and the aqueous phaseextracted with 304 L of toluene. The combined organic phases are washedwith a solution of 60.9 kg of NaCl in 305 L of water and concentratedunder reduced pressure at 60° C. The crude product is purified byfractional distillation at 125-160° C. under high vacuum. 34.3 kg ofintermediate (VII) were obtained. HPLC (method 1): area %: 99.56% VII;content: 99.9% by weight

Example 8 (7-Methoxy-5-methyl-1-benzothiophen-2-yl)boronic acid (VI)

357 L of THF are cooled to −68 to −80° C. and 118.2 kg of n-butyllithium(2.5M in hexane) are added at this temperature. The mixture issubsequently further cooled to −73 to −80° C. In a further reactionvessel, 51.0 kg of (VII) are dissolved in 87 L of THF and are addedslowly to the highly cooled n-butyllithium solution previously prepared.The reaction mixture is then stirred a further 30 minutes at the lowertemperature and 109 L of triisopropyl borate are then added at −70 to−80° C. After 30 min, 20.9 kg of KOH in 102 L of water are added at <10°C. The mixture is then further diluted with 663 L of water and theorganic phase separated at 20-30° C.

The aqueous phase is washed 3 times with 153 L of toluene, cooled to 0to 5° C. and slowly acidified to pH 2-3 with semi-concentrated sulphuricacid. After 3 h at 0 to −5° C., the mixture is filtered and the filterresidue washed with 510 L of water. The moist filter cake is suspendedin 510 L of cyclohexane at 40-45° C., isolated by filtration at 20-35°C. and washed on the filter with 255 L of cyclohexane.

The product is dried in the vacuum drying cabinet at 40-45° C. 64.8 kgof (VI) are obtained having a water content of ca. 10% to 15%.

HPLC (method 1) area %: 99.01% VI, 0.97% VII; content: 88.6% by weight

A sample for NMR characterization was produced following to theidentical procedure as described above, but on smaller laboratory scale:

¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.43 (s, 3H), 3.93 (s, 3H), 6.77 (s,1H), 7.29 (s, 1H), 7.86 (s, 1H), 8.44 (s, 2H)

Alternative Synthetic Intermediates Example 9 Methyl7-hydroxy-1-benzothiophene-5-carboxylate (XV)

22.6 g of intermediate (X) are initially charged in 560 mL of ethanoland 13.7 g of K₂CO₃ are added. The suspension is heated to reflux for 4h and subsequently concentrated under reduced pressure at 40° C.

560 mL of water and 560 mL of methyl t-butyl ether are added to theresidue and the pH is adjusted to 2-3 with 2M aqueous HCl. The phasesare separated and the aqueous phase is extracted with 3×230 mL of methylt-butyl ether. The combined organic phases are dried over sodiumsulphate and concentrated under reduced pressure at 40° C. 18.8 g ofintermediate (XV) are obtained in quantitative yield.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.87 (s, 3H), 7.34 (d, J=0.98 Hz, 1H),7.55 (d, J=5.26 Hz, 1H), 7.82 (d, J=5.38 Hz, 1H), 8.03 (d, J=1.10 Hz,1H), 10.73 (s, 1H)

LCMS (method 3): R_(t)=1.52 min; MS (ESI pos): m/z=209 (M+H)⁺

Example 10 5-(Hydroxymethyl)-1-benzothiophen-7-ol (XVI)

25.0 g of intermediate (XI) are initially charged in 250 mL oftetrahydrofuran and 117.1 g of a 60% solution of sodiumbis(2-methoxyethoxy)aluminium dihydride (Red-Al®) in toluene are addedat 15-20° C. over a period of 1.5 h. The reaction mixture is stirred fora further 20 h, cooled to 5-10° C. and subsequently 300 mL of 2M aqueoushydrochloric acid and 100 mL of water are added slowly. 350 mL of methylt-butyl ether are added and the mixture is filtered over diatomaceousearth with a further 100 mL of methyl t-butyl ether. The phases areseparated and the aqueous phase is extracted with 2×60 mL of methylt-butyl ether. The combined organic phases are washed with 50 mL ofwater, dried over to Na₂SO₄ and concentrated under reduced pressure at35° C. 18.4 g of intermediate (XVI) are obtained.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.53 (d, J=5.75 Hz, 2H), 5.16 (t, J=5.75Hz, 1H), 6.76 (s, 1H), 7.27 (s, 1H), 7.35 (d, J=5.26 Hz, 1H), 7.64 (d,J=5.26 Hz, 1H), 10.19 (s, 1H)

LCMS (method 1): R_(t)=0.58 min; MS (ESI pos): m/z=179 (M−H)⁻

1-6. (canceled)
 7. A compound of formula (XVI):


8. (canceled)
 9. A method of preparing Rogaratinib having a structure offormula (I):

comprising reacting a compound selected from the group consisting of: